Gene and stem cell research is showing promise for the treatment of chronic wounds
"Results from several studies using gene therapy are very exciting," says Dr. Kirsner, who notes that there is only one growth factor, Regranex (becaplermin or platelet-derived growth factor/PDGF, Ortho-McNeil), approved by the Food and Drug Administration (FDA) for treating chronic wounds.
"It has been on the market for about 10 years. The benefit is not as dramatic as the animal and in vitro studies would have indicated. Part of the problem is that growth factors are proteins and the wound environment is hostile, possessing many proteases whose function is to break down proteins. Because of this, many investigators note that the idea of having a growth factor is a good one, but there are other ways to deliver the growth factor to the wound other than just applying it topically," he says.
Margolis DJ et al recently published (Molecular Therapeutics) the results of a phase 1 study of H5.020CMV.PDGF-beta to treat venous leg ulcers. The authors noted that although topically applied growth factors improve wound repair in animal studies, similar studies on humans with venous leg ulcers have not been successful. In their study, they demonstrated the initial safety, feasibility and biologic plausibility of peri-ulcer injection of a replication-incompetent adenoviral construct expressing platelet-derived growth factor-beta (PDGF-beta) for the treatment of venous leg ulcer disease.
Positive results were released for a larger-scale woundcare study, the Matrix phase 2b clinical trial of Excellarate (Cardium Therapeutics) for the potential treatment of patients with chronic nonhealing diabetic foot ulcers based on the Gene Activated Matrix (GAM) technology platform. "These are early results of an interesting trial. It was the first large trial with several hundred patients using gene therapy for diabetic foot ulcers," Dr. Kirsner explains.
The study evaluated patients treated with the Excellarate (GAM501, a combination of Ad5PDGF-B and 2.6 percent collagen) or 2.6 percent collagen alone (matrix), compared to patients who received only the protocol-specified standard of care without any applied Ad5PDGF-B or collagen matrix.
"When diabetic foot ulcers were debrided and a gene-activated matrix (GAM) was applied to the wound, the cells which normally migrate into the wound site to help heal the wound were infected with adenovirus, and the cells subsequently made more PDGF. As this was a phase 2b study, additional studies will be needed before going to the FDA, but the results were positive," Dr. Kirsner says.
New chronic wound research has also provided a biological basis for debriding chronic wounds. "The cells, keratinocytes, at edge of wounds have been found to be genetically abnormal. They express certain markers, such as nuclear staining of beta-catenin and an oncogene, c-Myc.
"Additionally, if these are over-expressed in normal keratinocytes in culture, those affected keratinocytes do not behave normally. In acute wounds, nuclear staining of beta-catenin and c-Myc are not expressed, but as one moves away from the edge of the chronic wound to more normal tissues, in contrast to the edge of the wound, they are not expressed," Dr. Kirsner says.
Investigators including Marianna Tomic-Camic, Ph.D., Olivera Stojadinovic, M.D., and Harold Brem, M.D., have shown that as doctors debride, the goal should be to remove genetically abnormal tissue to get to more normal tissues. "This research provides a rationale mechanism and gives a better understanding why debridement might help and to the extent wounds should be debrided. It is envisioned that someday we may have simple tests to tell where a clinician should extend their debridement, sort of a 'Mohs surgery' for debridement," he says.
Stem cell studies
Stem cell research is also providing new clues in woundcare. A study by Lui et al, published in the Journal of Cellular Biochemistry, looked at mesenchymal stem cells (MSCs), a heterogeneous population of stem/progenitor cells with the pluripotent capacity to differentiate into mesodermal and non-mesodermal cell lineages. MSCs exist primarily in bone marrow, but also are in sites such as adipose tissue, peripheral blood and cord blood.
The study, which demonstrated the feasibility for transplantation of primary or engineered MSCs as cell-based therapy, showed that when stimulated by specific signals, these cells can be released from their niche in the bone marrow into circulation and recruited to the target tissues, where they undergo in situ differentiation and contribute to tissue regeneration and homeostasis. This study, as well as a study by Milovanova et al on hyperbaric oxygen (published in the Journal of Applied Physiology), offer clues as to the process in diabetic wound and potential new treatments, Dr. Kirsner says.
Other innovators in woundcare, such as Evangelos Badiavas, M.D., Ph.D., and Vincent Falanga, M.D., are researching new ways of delivering bone marrow-derived stem cells from the bone marrow to the wound. "They and others are studying novel methods of placing bone marrow-derived cells directly or after selective or nonselective culture onto wounds," he says, noting that while each researcher takes a different approach, the concept remains to use bone marrow-derived stem cells to speed healing.
The research, while early, is encouraging, Dr. Kirsner concludes.